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P. Lara Jr.

Moderator of

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    ED 07 - How to Treat Advanced Squamous Carcinoma of the Lung (ID 7)

    • Event: WCLC 2015
    • Type: Education Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 5
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      Introduction (ID 2054)

      02:15 - 02:20 PM

      • Abstract

      Abstract not provided

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      ED07.01 - Overview of the Histology and Potential Driver Mutations (ID 1798)

      02:20 - 02:40 PM  |  Author(s): P. Hammerman

      • Abstract
      • Presentation
      • Slides

      Abstract:
      While genomic studies of lung adenocarcinomas over the past decade have enabled substantial improvements in treatment and patient outcomes, advances in squamous cell carcinomas of the lung have been far more modest. At present there are no targeted agents approved for the treatment of squamous cell lung cancers and there has been limited success in the use of targeted kinase inhibition in this disease. Here, I will review the results of genomic studies of squamous cell carcinomas and highlight the molecular features which drive these cancers and make them distinct from lung adenocarcinomas. I will discuss specific subtypes of squamous cancers, animal models of the disease and associations among genomic features and patient outcomes. I will discuss therapeutically relevant genetic alterations and efforts aimed at exploring these targets both pre-clinically and clinically with an emphasis on FGFR pathway genes. I will discuss heterogeneity and adaptive responses to therapy in squamous cell carcinomas as potential challenges to the treatment paradigms which have been successful in adenocarcinomas and these concepts in the context of the recent introduction of immunotherapeutic approaches.

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      ED07.02 - Current State of the Art (ID 1799)

      02:40 - 03:00 PM  |  Author(s): G. Goss, J. Spaans

      • Abstract
      • Presentation

      Abstract:
      Squamous cell carcinoma of the lung accounts for 20-30% of all non-small cell lung cancer (NSCLC). Until recently, treatment options for advanced squamous NSCLC (sqNSCLC) were limited. Compared to non-squamous NSCLC, standard care of sqNSCLC was restricted to first-line platinum-based doublet chemotherapy and second-line docetaxel or the epidermal-growth factor receptor (EGFR) inhibitor, erlotinib, and did not include pemetrexed because of inferior efficacy[1], bevacizumab because of increased risk of pulmonary hemorrhage[2] or agents active against known oncogenic driver mutations. Prompted by the high levels of EGFR overexpression in sqNSCLC and encouraging activity of EGFR-targeted therapies in patients with squamous histology [3,4] EGFR-inhibition trials limited to patients with sqNSCLC were initiated, the results of which are redefining the treatment of sqNSCLC. In the first-line setting, the addition of the second-generation recombinant human IgG1 EGFR monoclonal antibody (Mab), necitumumab, to gemcitabine and cisplatin has been shown to improve overall survival (OS) 11.5m vs 9.9 m (HR: 0.84, 95%CI: 0.74-0.96) in the phase III open-label SQUIRE trial, with comparable adverse events (AE) leading to treatment discontinuation in both treatment arms.[5] The better tolerability of necitumumab over the first-generation chimeric EGFR Mab, cetuximab, is supported by the similar OS efficacy in patients with good (PS: 0-1) (HR: 0.85, 95%CI: 0.74-0.98) and poor performance status (PS=2) (HR: 0.78, 95%CI: 0.51-1.21), in the absence of additional safety risk.[6] In fact, in SQUIRE, necitumumab was notably more effective at higher levels of baseline symptom severity[7] , which is contrary to the belief that patients with sqNSCLC deteriorate too quickly to benefit from combination approaches. In the second-line setting, the newer second-generation EGFR small molecule inhibitor, afatinib, has also been shown to improve OS. Most recently, the results of the phase III LUX-Lung 8 trial of afatinib vs erlotinib in patients with sqNSCLC progressing after four cycles of platinum-based chemotherapy have been published, demonstrating improved OS with afatinib 7.9m vs 6.8m (HR: 0.81, 95%CI: 0.69-0.95), with similar adverse events profiles noted between groups.[8 ]Based on these results, afatinib is clearly a treatment option for patients in the second-line management of sqNSCLC. Together, the recent results of these small molecule and MAb anti-EGFR studies support the continued relevance of EGFR as a target in the treatment of sqNSCLC and are shaping management strategies. Despite being a hallmark of cancer, the inhibition of angiogenesis has historically proven challenging in the treatment of patients with sqNSCLC due to the central location of these tumors and their close proximity to large blood vessels in the chest wall, and has been associated with an increased risk of bleeding. Findings from newer second-generation angiogenesis inhibitors, however, show comparable levels of gastrointestinal and respiratory tract bleeding events across all NSCLC histologies. [9 ] Compared to placebo, the anti-VEGFR-2 IgG MAb, ramucirumab, has recently been shown to improve progression-free survival (PFS) 4.5m vs 3.0 m (HR: 0.76, 95%CI: 0.68-0.86) and OS 10.5m vs 9.1m (HR: 0.86, 95%CI:0.75-0.98) in patients with advanced NSCLC progressing after first-line platinum-based chemotherapy, with significant improvements in patients with squamous histology in terms of overall objective response (ORR) (26.8% vs 10.5%, p=0.001), disease control rate (59.9% vs 45%, p=0.015) and PFS 4.2m vs 2.7m (HR 0.78, 95%CI0.61-0.96) and a numerically superior OS benefit 9.5m vs 8.2m (HR: 0.88, 95%CI: 0.69-1.13). [9 ] In Dec 2014, ramucirumab received FDA approval for use with docetaxel in the second-line management of advanced NSCLC, including patients with squamous histology. Finally, the inhibition of T-cell activation through programmed death (PD-1) receptor interaction with the tumor expressing PD-L1 ligand (immune checkpoint) is a noted mechanism of tumor immune surveillance escape in NSCLC. From early clinical trials immune checkpoint blockade is an attractive therapeutic strategy in NSCLC, given its ability to activate the immune system and produce long-term response. In the management of sqNSCLC, the fully human IgG4 anti-PD-1 monoclonal antibody, nivolumab, has recently replaced docetaxel as the preferred second-line therapy based on the results of CHECKMATE 017 [10], a phase III study of nivolumab versus docetaxel. Findings in CHECKMATE 017 demonstrated improved median OS 9.2m vs 6.0m (HR: 0.59, 95%CI: 0.44-0.79) and improved 1-year survival over docetaxel (42% vs 24%), with a more favorable safety profile and fewer treatment related grade 3/4 AE (7% vs 55%).[10] With the recent FDA approval of nivolumab in the second-line setting in March 2015, docetaxel will likely be relegated to third-line therapy in the management of sqNSCLC. However, additional studies are required to confirm the results of CHECKMATE 017 given the lower than expected median survival observed in the docetaxel arm, to identify biomarkers of response, and to better define the unique toxicities associated with these immune-modulating agents. The last year has seen an unprecedented evolution in the management of sqNSCLC, with survival gains noted in both the first and second-line setting in randomized clinical trials. Unfortunately, to date the identification of oncogenic driver mutations in sqNSCLC have yet to yield the significant improvements seen in non-squamous histology, however it is likely that the relevant biomarkers of efficacy will soon be identified. Regardless, with the current regulatory approvals and the numerous novel agents in development, improved outcomes in patients with squamous cell carcinoma of the lung are anticipated. The immediate task, with the expanded treatment options now available for sqNSCLC, is the interrogation of new combinations and the sequencing of available therapies to maximize the benefit for this historically underserved subgroup of patients with NSCLC. References 1. Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in non-squamous non-small cell lung cancer. J Thorac Oncol 2011; 6: 64-70. 2. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 2004; 22: 2184-91. 3. Pujol JL, Pirker R, Lynch TJ et al. Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer 2014; 83: 211-218. 4. Kim JH, Grossi F, De Marinis F et al. Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy : interim subset analysis from a phase III trial. Proc Am Soc Clin Oncol 2012; 30 (suppl 15): abstr 7558. 5. Thatcher N, Hirsch F, Luft A et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomized, controlled phase 3 trial. Lancet Oncol 2015; 16(7): 763-774. 6. Socinski M, Luft A, Szczesna A et al. Subgroup analyses by performance status (PS) in the phase III SQUIRE study: First-line necitumumab (N) plus gemcitabine-cisplatin (GC) vs. GC in squamous non-small cell lung cancer (NSCLC). J Clin Oncol 2015; 33:suppl; abstr e19023. 7. Reck M, Gralla RJ, Bonomi P et al. Maximum severity score (MSS) of baseline patient-reported Lung Cancer Symptom Scale (LCSS) as a prognostic and predictive factor for overall survival (OS) in the Phase III SQUIRE study. ASCO Meeting 2015 abst; 33: 8099. 8. Soria J-C, Felip E, Cobo M et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; dx.doi.org/10.1016/s1470-2045(15)00006-6. 9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomized phase 3 trial. Lancet 2014; 384: 665-73. 10. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in advanced squamous-cell non small cell lung cancer. NEJM 2015; doi: 10.1056/NEJMoa1504627.

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      ED07.03 - Lung Master Protocol in Squamous Cell Lung Cancer (Lung-MAP, S1400) (ID 1800)

      03:00 - 03:20 PM  |  Author(s): D.R. Gandara, M. Redman, R. Herbst, J. Abrams, S. Malik, E. Sigal, F.R. Hirsch, P.C. Mack, V. Papadimitrakopoulou

      • Abstract
      • Presentation

      Abstract:
      In recent years, our understanding of non-small cell lung cancer (NSCLC) has evolved from thinking of this malignancy as a single disease, or a small number of histologic subtypes, to now a multitude of genomically-defined subsets, both in adenocarcinoma and squamous lung cancer. In development of new targeted therapies against these abnormalities, so-called Master Protocols offer a number of advantages over traditional single study designs for drug-biomarker approval, including a common infrastructure, homogeneous patient populations with consistent eligibility across multiple independent sub-studies, and the ability to screen large numbers of patients in rapid fashion. Thus, the Lung-MAP project was designed to facilitate approval of targeted therapy-predictive biomarker combinations in squamous lung cancer, a recognized area of unmet need. Lung-MAP is constructed as a unique public-private partnership engaging the National Cancer Institute (NCI) and its Thoracic Malignancies Steering Committee (TMSC), the Foundation of the NIH (FNIH), the pharmaceutical industry and advocacy groups such as Friends of Cancer Research (FOCR), along with an advisory role by the Federal Drug Administration (FDA). The design is multiple simultaneously running Phase II/III trials, each capable of independently opening and/or closing without affecting the other sub-studies, in which patients eligible for 2[nd] line therapy for lung SCC have their cancers genomically screened through a next generation sequencing (NGS) platform (Foundation Medicine). Patients are then randomized into one of several sub-studies, each comparing an experimental targeted therapy with standard of care therapy, based on identification of candidate predictive biomarkers associated with each sub-study. At launch, drug targets under study consisted of “match sub-studies” for PI3K, FGFR, CDK 4/6 and HGF, and a non-match sub-study testing PD-L1-directed therapy, as described below. Rapid turn-around time of NGS screening results, within 2 weeks, allows real time assignment into the appropriate sub-study. For those patients with cancers that do not “match” into a biomarker-driven sub-study, there is a ‘non-match” sub-study, in which a predictive biomarker is not yet of sufficient validation to utilize it in a drug-biomarker registration strategy. Due to changes in the therapeutic landscape since the launch of Lung-MAP, a number of amendments and modifications have been implemented, which will be discussed during this presentation.

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      ED07.04 - Targeting Gene Amplification in Squamous Cancer (ID 1801)

      03:20 - 03:40 PM  |  Author(s): P. Paik

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Copy number alterations are common events in squamous cell lung cancers. A number of these play defined roles in tumorigenesis. Some are known to be oncogenic drivers in a subset of cases. Broad high-level amplification of the 3q26-28 cytoband occurs in about 30% of squamous cell lung cancers and was one of the first recurrent alterations characterized in this disease.(1) More focal amplification of 8p11 occurs between 10-20% of tumors.(2, 3) Specific genes in 3q26 that are recurrently amplified include SOX2, PIK3CA, and PRKCI. Other genes commonly amplified in 3q27-28 include BCL6, TP63, and EPHB3. Genes that are amplified at lower frequencies include EGFR, MYC, MCL1, RICTOR, CCND1, and CDK6. The table below summarizes these alterations.

      Gene Chromosome Frequency
      SOX2 3q26 35%
      PIK3CA 3q26 30%
      BCL6 3q27 20%
      PRKCI 3q26 25%
      TP63 3q28 21%
      FGFR1 8p11 12%
      MYC 8q24 8%
      MCL1 1q21 6%
      RICTOR 5p13 6%
      EGFR 7p12 5%
      CCND1 11q13 10%
      CDK6 7q21-22 3%
      Pharmacologic targeting of gene amplification events in squamous cell lung cancers has centered largely on 4 genes- FGFR1, PIK3CA, CCND1, and CDK6. The pre-clinical data and clinical trial work defining FGFR1 amplification as an oncogenic driver and drug target, respectively, are the most mature. Three abstracts summarizing the preliminary efficacy of the pan-FGFR inhibitors AZD4547, BGJ398, and JNJ42756493 were presented in 2014.(4-6) The overall response rates were low, ranging from 8-15%. Some of these have continued on as phase 2 trials (NCT02154490, AD4547). Other studies using less-specific FGFR inhibitors are also ongoing (NCT01935336, ponatinib; NCT02109016, lucitanib). Upstream PI3K pathway alterations have been the therapeutic targets for a number of trials of PI3K inhibitors, though only a subset have included PIK3CA amplification as a biomarker of interest. These include two phase 1 trials of PI3K-α or PI3K/mTOR inhibitors that have added expansion arms for PIK3CA amplified squamous cell lung cancers (NCT01296555, GDC0032; NCT01655225, LY3023414). Data for these studies have not yet been presented. Finally, G1/S checkpoint inhibitors, whose efficacy has been best defined in breast cancer, are now being tested for CCDN1 and CDK4/6 amplified squamous cell lung cancers. Drugs include palbociclib (S1400, NCT02154490) and abemaciclib (NCT02450539). It is worth noting, however, that the pre-clinical rationale for targeting the G1/S checkpoint alone is substantially weaker than for other pathways. The clinical experience derived from targeting FGFR1 amplification in squamous cell lung cancers can serve as a framework to understand, in general, which targeted therapy strategies are likely to fail both now and in the future. Comprehensive genomic analyses of squamous cell lung cancers have shown that these tumors are complex, with overlapping alterations in more than one oncogene and/or tumor suppressor occurring in most cases. This is particularly problematic for gene amplification targets, which are also plagued by questions of functional relevance apropos degree of amplification and association with protein expression. As borne out in the phase 1 trials of the pan-FGFR inhibitors, single-target inhibition is unlikely to generate the breadth and depth of responses seen with other drugs targeting other oncogenes. Issues surrounding pharmacodynamic efficacy and target inhibition may also play a role in limiting responses. Data from ongoing work will be presented identifying potential genomic and non-genomic modifiers of response to FGFR1 inhibition. References 1. Björkqvist A-M, Husgafvel-Pursiainen K, Anttila S, Karjalainen A, Tammilehto L, Mattson K, et al. DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma. Genes, Chromosomes and Cancer. 1998;22:79-82. 2. Paik PK, Shen R, Won H, Rekhtman N, Wang L, Sima CS, et al. Next generation sequencing of stage IV squamous cell lung cancers reveals an association of PI3K aberrations and evidence of clonal heterogeneity in patients with brain metastases. Cancer Discovery. 2015. 3. TCGA. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-25. 4. Paik P, Shen R, Ferry D, Soria J-C, Mathewson A, Kilgour E, et al. A phase 1b open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers: Preliminary antitumor activity and pharmacodynamic data. J Clin Oncol. 2014;32:suppl; abstr 8035. 5. Nogova L, Sequist L, Cassier P, Hidalgo M, Delord J-P, Schuler M, et al. Targeting FGFR1-amplified lung squamous cell carcinoma with the selective pan-FGFR inhibitor BGJ398. J Clin Oncol. 2014;32:suppl; abstr 8034. 6. Bahleda R, Dienstemann R, Adamo B, Gazzah A, Infante J, Zhong B. Phase 1 study of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014;32:abstr 2501.

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    ORAL 10 - SCLC (ID 98)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Small Cell Lung Cancer
    • Presentations: 9
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      Lectureship Award Winner (ID 3651)

      10:45 - 11:05 AM

      • Abstract
      • Slides

      Abstract not provided

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      ORAL10.01 - A DLL3-Targeted ADC, Rovalpituzumab Tesirine, Demonstrates Substantial Activity in a Phase I Study in Relapsed and Refractory SCLC (ID 1598)

      11:05 - 11:16 AM  |  Author(s): C.M. Rudin, M.C. Pietanza, D.R. Spigel, T. Bauer, B. Glisson, F. Robert, N. Ready, D. Morgensztern, M.D. Kochendoerfer, M. Patel, R. Salgia, D.K. Strickland, R. Govindan, H. Burris, S.J. Dylla

      • Abstract
      • Slides

      Background:
      Rovalpituzumab tesirine (i.e. SC16LD6.5) is a Delta-like protein 3 (DLL3) targeted antibody-drug conjugate (ADC) comprised of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio of 2. DLL3 is highly expressed in human neuroendocrine tumors and their tumor-initiating cells, including approximately two-thirds of small cell lung cancer (SCLC). DLL3 is not expressed at detectable levels in normal tissues. Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin/etoposide in DLL3-expressing SCLC patient-derived xenograft tumor models. Based on this promising activity, a first-in-human phase I trial in patients (pts) with recurrent SCLC was initiated and preliminary results are reported below.

      Methods:
      SCLC pts with progressive disease after 1 or 2 previous lines of therapy received escalating doses of rovalpituzumab tesirine as a single agent once every 3 weeks (Q3W) in 1-3 pt cohorts until dose limiting toxicities (DLTs) were observed. The doses were 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg Q3W. Midway through accrual, pharmacokinetic data revealed a longer than expected ADC half-life of ~11 days, prompting evaluation of a Q6W schedule. A DLL3 antibody was developed and utilized to assess antigen expression in archived tumor specimens. Biomarker positive (BM+) tumors were defined by IHC membrane-associated H-Scores ≥ 120.

      Results:
      52 pts were treated: 34 Q3W and 18 Q6W; 24F/28M; median age, 61 years (44-82). Acute and chronic DLTs of thrombocytopenia and capillary leak syndrome (CLS) were observed at 0.8 and 0.4 mg/kg Q3W, respectively. Maximum tolerated doses (MTD) of 0.2 mg/kg Q3Wx3 cycles and 0.3 mg/kg Q6Wx2 cycles were further evaluated in expansion cohorts. The most common treatment emergent adverse events of any grade among all pts were fatigue (40%), rash (39%), nausea (29%), dyspnea (23%), decreased appetite (21%) and vomiting (21%). Grade 3+ CLS and thrombocytopenia were seen in 7 (14%) and 3 (6%) pts, respectively, with no reported Grade 5 toxicity. Of 38 archived tumor specimens received from enrolled pts, 23 (61%) were DLL3 BM+. Among the 16 confirmed DLL3 BM+ pts treated at the MTDs, 7 pts (44%) had partial response (PR) and 8 pts (50%) achieved stable disease (SD) for a combined clinical benefit rate (CBR) of 94%. In all evaluable pts treated at the MTD without regard for DLL3 biomarker status (n=32), the ORR was 22% (n=7 PR) and SD 53% (n=17), for a CBR of 75%. Notably, all pts with PRs that were treated at the MTD, and those having the most durable clinical benefit (up to 569 days OS), were BM+. Similar response rates were observed among pts sensitive and refractory to first-line therapy, and in the third-line setting where no standard-of-care currently exists.

      Conclusion:
      Rovalpituzumab tesirine, a first-in-class DLL3-targeted ADC, has manageable toxicity and demonstrated significant anti-tumor activity (44% ORR and 95% CBR) as a single agent in second- and third-line pts with recurrent DLL3 BM+ SCLC. A pivotal study is being planned.

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      ORAL10.02 - A Prospective Randomized Phase III Study of Continuum Chemotherapy versus Chemo-Radiotherapy in ES-SCLC in Asian Indian (ID 2854)

      11:16 - 11:27 AM  |  Author(s): S. Narayan, M. Singhal, S. Beniwal, A. Kapoor, N. Sharma, R. Saught, A. Sharma

      • Abstract

      Background:
      Selected patients with good responses to platinum based chemotherapy and good performance status were candidates for continuum platinum based chemotherapy versus chemo-radiotherapy in Extensive-stage small cell lung cancer (ES-SCLC). To evaluate the efficacy and toxicity of continuum platinum based chemotherapy versus chemo-radiotherapy in ES-SCLC in Asian Indian patient population.

      Methods:
      Between July 2008 and December 2009, 358 patients with ES-SCLC treated with induction Cisplatin (60-80mg/m2 d1) + Etoposide (80-120 mg/m2 d1-3) × 3 cycles for every 3 weeks. Patients with CR at both local as well as distant sites or PR at the local site, but CR at distant sites were randomized 1:1 to two treatment groups (n=287). A total of 287 patients with response were randomized to accelerated hyperfraction thoracic RT (45Gy/1.5 Gy twice daily) plus PE × 4 (144) versus PE × 4 alone without radiation (n=143). The PE doses were similar as in induction. All patients received prophylactic cranial irradiation (25Gy/10 fraction/5/week). The primary endpoint was the comparison of progression free survival (PFS) between the two arms and the secondary endpoints included overall survival (OS). All statistical analyses were performed by using SPSS version 20.0.

      Results:
      Baseline characteristics were well balanced. Mean age was 58 years (range 32-69), 78% had ECOG 0-1; 22% ECOG 2. In the CRT arm 66.67% and in CT only arm 57.34% patients were smoker. Median PFS 15 months (CRT arm) versus 10 months (CT only) (HR, 0.78; 95% CI, 0.56-1.18; p=0.06) and 5-year OS 10.3% (CRT arm) versus 6.2% (CT only) (HR, 0.83; 95% CI, 0.49 to 1.29; p=0.47) respectively. The survival difference at 1 year was not statistically significant (39% vs 31%; HR=0.89, CI 0.69-1.13; p=0.091). The survival difference at 3 years was just significant (18% vs 11%; HR=0.83, CI 0.72-1.08; p=0.047). Local control trended better in CRT arm, but no difference in distant metastasis control in both arms.

      Conclusion:
      CRT arm showed better PFS and OS than CT only arm within Asian Indian patient population. Thus, the CRT may be used as a continuum treatment in Asian Indian patients of ES-SCLC after induction chemotherapy.

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      ORAL10.03 - Which Patients with ES-SCLC Should Receive Thoracic Radiotherapy (TRT) Routinely? (ID 41)

      11:27 - 11:38 AM  |  Author(s): B. Slotman, C. Faivre-Finn, H. Van Tinteren, J. Praag, J. Knegjens, S. El Sharouni, M. Hatton, A. Keijser, S. Senan

      • Abstract
      • Presentation
      • Slides

      Background:
      Although TRT in patients with ES-SCLC did not lead to a statistically significant difference in overall survival (p=0.066), it did improve 2-year survival rates (p=0.004) in the CREST trial (Slotman et al., Lancet 385:36-42:2015). The failure to meet the primary study endpoint has evoked some controversy in the lung cancer community as to which patients should be offered TRT routinely. To define which patients benefit most from radiotherapy, analysis for overall survival (OS), progression free survival (PFS) and recurrence pattern was performed in patients with and without RITD, which was one of the stratification factors in the randomized study.

      Methods:
      Patients with confirmed ES-SCLC who responded to 4-6 cycles of platinum-etoposide were randomized to TRT (30 Gy/10fx) or control. All received prophylactic cranial irradiation (PCI). The primary study endpoint was OS. Secondary endpoints were PFS, intrathoracic control. relapse pattern and toxicity.

      Results:
      Out of 495 patients in the intent-to-treat analysis, 434 had RITD (215 allocated to TRT and 219 to the control arm) and 61 had not (32 allocated to TRT and 29 to the control arm). No significant differences in patient characteristics were observed between the groups. In patients with RITD, OS was significantly longer in the TRT-arm (HR 0.81,95% CI 0.66-1.00;p=0.044). Survival rates in the TRT and control arm were 33% (95%CI 27-40) vs 26% (95%CI 21-33) at 1 year, and 12% (95%CI 8-19) vs. 3% (95%CI 1-8) at 2 years, respectively. PFS was also significantly longer in the TRT-arm (HR=0.70, 95%CI 0.57-0.85; p<0.001). Intrathoracic progression was reported in 43.7% of the TRT arm vs. 81.3% in the control arm (p<0.001). There was no significant difference in the risk of brain metastases (10.2% vs. 5.5%). Exclusive progression outside thorax and brain occurred in 37.2% in the TRT arm, compared to 5.9% in the control arm (P<0.001). In patients without RITD, there was no significant difference in OS (HR 1.02, 95%CI 0.59-1.77, p=0.937) and PFS (HR=1,00, 95%CI 0.59-1.70, NS) between the TRT and control arms.

      Conclusion:
      This additional analysis of the CREST data shows that ES-SCLC patients with RITD after chemotherapy have a statistically significant improvement in OS, PFS and risk of intrathoracic progression if they undergo TRT. No such benefit for TRT is seen in patients without RITD. These findings support the routine use of TRT in patients who respond to chemotherapy but still have residual intrathoracic disease.

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      ORAL10.04 - Pembrolizumab for ED SCLC: Efficacy and Relationship with PD-L1 Expression (ID 3285)

      11:38 - 11:49 AM  |  Author(s): P.A. Ott, E. Elez, S. Hiret, D. Kim, R.A. Moss, T. Winser, S.S. Yuan, M. Dolled-Filhart, J. Cheng, B. Piperdi, J.M. Mehnert

      • Abstract
      • Presentation
      • Slides

      Background:
      Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized IgG4 monoclonal antibody against PD-1 designed to block the interaction between PD-1 and its ligands PD-L1 and PD-L2, has demonstrated robust antitumor activity and a manageable toxicity profile in several advanced cancers, including NSCLC. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1–positive SCLC in the ongoing, multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov, NCT02054806).

      Methods:
      Key eligibility criteria for the SCLC cohort include failure of or inability to receive standard therapy, ≥1 measurable lesion per RECIST v1.1, ECOG performance status 0 or 1, PD-L1 expression in ≥1% of cells in tumor nests or PD-L1–positive bands in stroma as assessed by IHC using the 22C3 antibody at a central laboratory, no autoimmune disease, no interstitial lung disease, and no prior anti–PD-1 or anti–PD-L1 therapy. Pembrolizumab is given at 10 mg/kg every 2 weeks for 24 months or disease progression, intolerable toxicity, or investigator decision. Patients with progressive disease who are clinically stable may continue treatment until confirmation of progression 4 weeks later. Response will be assessed per RECIST v1.1 by investigator review every 8 weeks for the first 6 months, then every 12 weeks thereafter. Adverse events (AEs), including potentially immune-related adverse events, will be collected throughout the study and for 30 days (90 days for serious AEs) thereafter. Primary end points are safety and tolerability and the overall response rate. The relationship between pembrolizumab antitumor activity and potential biomarkers, including the level of PD-L1 expression, is an exploratory end point.

      Results:
      Of the 147 patients with SCLC who had evaluable tumor samples and were screened for PD-L1 expression, 42 (29%) had PD-L1–positive tumors. Overall, 24 patients with SCLC were enrolled and received ≥1 pembrolizumab dose. Among the 20 patients treated as of March 13, 2015, median age was 59.5 years, 55% were men, and 75% had an ECOG performance status of 1. All patients had received prior chemotherapy with a platinum + etoposide.

      Conclusion:
      Analyses of safety and tolerability and response are ongoing, as are analyses on the relationship between the level of PD-L1 expression and pembrolizumab response. These data will be available for presentation.

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      ORAL10.05 - Discussant for ORAL10.01, ORAL10.02, ORAL10.03, ORAL10.04 (ID 3560)

      11:49 - 11:59 AM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ORAL10.06 - Long-Term Survival after Surgery for Pathologic N1 and N2 Small Cell Lung Cancer: A Comparison with Nonoperative Management (ID 3089)

      11:59 - 12:10 PM  |  Author(s): C.J. Yang, D.Y. Chan, P.J. Speicher, B.C. Gulack, M.W. Onaitis, M.G. Hartwig, B.C. Tong, M.F. Berry, T.A. D'Amico, D. Harpole

      • Abstract
      • Presentation
      • Slides

      Background:
      With the advent of modern chemotherapy, patients previously thought to have unresectable small cell lung cancer (SCLC) may have tumors amenable to surgery. This study was undertaken to test the hypothesis of whether surgery, in the setting of modern adjuvant therapies, offers a survival advantage among patients with node-positive SCLC.

      Methods:
      Overall survival (OS) of patients with pT1-2 pN1-2 M0 SCLC who underwent non-operative management (chemotherapy ± radiation) vs surgery (with adjuvant chemotherapy ± radiation) in the National Cancer Data Base (NCDB) from 2003-2011 was assessed using propensity-score-matched analysis. Groups were matched for common prognostic co-variates (year of diagnosis, age, sex, race, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, pathologic T and N status, and tumor location). NCDB data is prospectively collected by certified tumor registrars and include over 70% of cancer cases diagnosed annually in the U.S.

      Results:
      Of 1,071 patients who met inclusion criteria, 359 (33.5%) patients underwent surgery with adjuvant chemotherapy ± radiation and 712 (66.5%) underwent non-operative management. After propensity-score matching, 11 covariates were balanced between the surgery (n=231) and non-operative (n=231) groups. Surgery was associated with a significantly higher OS than non-operative management (5-year OS 28.1% vs 18.3, log-rank p<0.01) (Figure 1). To minimize treatment selection bias due to comorbidities, we limited the propensity-matched analysis to patients with no comorbidities; surgery remained significantly associated with a higher OS than non-operative management (5-year OS 32.1% vs 21.8%, log-rank p<0.01) (Figure 2). Figure 1 Figure 2





      Conclusion:
      In a propensity-matched analysis of a national population-based cancer database, surgery followed by adjuvant chemotherapy ± radiation for SCLC pT1-3 pN1-2 patients had improved outcomes when compared to non-operative medical treatment. These results support an increased role of surgery in multimodality therapy for more advanced limited-stage small cell lung cancer.

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      ORAL10.07 - Clinical and Molecular Profiling of Surgically Resected Small Cell Lung Cancer (ID 2235)

      12:10 - 12:21 PM  |  Author(s): K. Takamura, H. Yokouchi, H. Nishihara, H. Suzuki, H. Uramoto, S. Yamazaki, H. Kikuchi, K. Akie, F. Sugaya, Y. Fujita, M. Harada, T. Harada, M. Higuchi, T. Kojima, T. Fukuhara, Y. Matsuura, O. Honjo, Y. Minami, N. Watanabe, H. Dosaka-Akita, H. Isobe, M. Nishimura, M. Munakata

      • Abstract
      • Presentation
      • Slides

      Background:
      NCCN, ACCP and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC), while ESMO guidelines recommend surgery for patients with c-stage II (T1,2 N0,1). In addition, the clinical impact of surgery with other variables on patients with early-stage SCLC has yet to be determined. Therefore, clarification of the clinical profile of surgically resected SCLC is required. Suppression of MED12, a subunit of the transcriptional MEDIATOR complex in conjunction with cell surface expression of TGF-βRII was reported to be correlated with the resistance mechanism of EGFR-TKIs, crizotinib, and chemotherapy. Few investigators examined the expression profile of MED12 as well as receptor tyrosine kinases in SCLC. A next-generation sequencing (NGS) system is a novel technology for sequencing genomes at high-throughput and with great accuracy using deep sequencing. It has been instrumental for translational study integrating the detection of genetic alteration analysis into the better understanding of tumor biology, as well as treatment of various types of cancers. Recently, SOX-2 amplification, histone modification, and genetic alterations in the PI3K/AKT/mTOR pathway were reported to be potential targets of SCLC using NGS through whole exon analysis. However, further investigation is needed for the personalized treatment of SCLC. We updated the molecular data using NGS, which had been presented at ESMO 2014 (abstract ID: 5724).

      Methods:
      We reviewed the clinical courses of 156 patients with SCLC who had undergone surgery at 17 institutes from January 2003 through January 2013. One hundred twenty-five formalin-fixed paraffin-embedded tissue samples were subjected to immunohistochemistry using seven antibodies (MED12 and TGF-βRII, ALK, c-Met, EGFR, c-kit, and VEGFRII) and to NGS systems using MiSeq and TruSight Tumor Sequencing Panel (Illumina) loading 26 cancer-specific genes. (UMIN registration No. 000010116 /10117).

      Results:
      Median relapse-free survival and overall survival (OS) were 15.6 (95%CI=6.8-24.5) and 33.3 (20.9-45.8) months, respectively. Multivariate analysis revealed that OS was longer in patients without a history or presence of other types of cancer (HR: 0.545, 95%CI=0.335-0.887, p=0.014), with preoperative diagnosis (HR: 0.510, 95%CI=0.299-0.871, p=0.014), with c-stage II and under (HR: 0.288, 95%CI=0.154-0.541, p<0.001) and with prophylactic cranial irradiation (HR: 0.300, 95%CI=0.092-0.976, p=0.045). Of the 125 patients whose samples were available, MED12 and TGF-βRII were highly expressed in nucleus and cytoplasm, respectively in 92% and 55% of the samples. None of the tumors expressed ALK. There was no relationship between the expression of c-Met, EGFR, and VEGFRII and either of RFS or OS. Multivariate analysis demonstrated that high expression of c-kit in tumor is an independent factor for longer OS (HR=0.543, 95%CI: 0.310-0.953, p=0.033). Seventy-nine samples have been subjected to NGS. Three actionable gene mutations, EGFR (E746_A750del), KRAS (G12D), and AKT1 (E17K) were found.

      Conclusion:
      These results supported the ESMO guidelines for the management of early-stage SCLC, and indicated that presence or history of other types of cancer might be a major decisive factor for surgery. The results of immunohistochemistry using antibodies of selective molecules and NGS assist us in gaining a better understanding of the biology and treatment strategy of SCLC.

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      ORAL10.08 - Discussant for ORAL10.06, ORAL10.07 (ID 3330)

      12:21 - 12:31 PM  |  Author(s): D. Ball

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MINI 08 - Prognostic/Predictive Biomarkers (ID 106)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI08.04 - VeriStrat® and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib +/- Erlotinib in Non-Small Cell Lung Cancer (ID 552)

      05:10 - 05:15 PM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Background:
      VeriStrat is a blood-based multivariate proteomic test that predicts response to second line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy in non-small cell lung cancer (NSCLC). We report a retrospective blinded analysis of VeriStrat classification in plasma samples from a phase 1b/2 trial of cabozantinib (C) +/- erlotinib (E) in metastatic NSCLC patients who had all progressed after benefiting from EGFR TKI therapy. Cabozantinib inhibits the MET/hepatocyte growth factor (HGF) pathway, and VeriStrat may be a surrogate marker for this pathway.

      Methods:
      Patients enrolled into phase 1b (1A:60 mg C+150 mg E, 2A:60 mg C+100 mg E, 3A:100 mg C+100 mg E, 4A:100 mg C+50 mg E, 2B:40 mg C+150 mg E) and phase 2 (Arm A:100 mg C, Arm B:100 mg C+50 mg E). EGFR mutation (EGFRm) status was tested on archival tissue and/or plasma when available. The primary objective was to determine if pre-treatment VeriStrat (VS) classification, good or poor, was prognostic for patients treated with cabozantinib +/- erlotinib. Kaplan-Meier method and log-rank test was used to compare progression-free survival (PFS) of VS-good v. VS-poor patients. Outcomes were stratified by EGFRm status (mutated v. wild type WT/unknown UNK).

      Results:
      Of 79 evaluable patients, 71 were classified as VS-good and 8 as VS-poor. 55.7% had an activating EGFRm (majority exon 19 del/exon 21 L858R) and 12.7% had UNK EGFRm status. There were no significant differences in patient characteristics between VeriStrat-groups. VS-good patients had a statistically improved PFS: VS-good 3.7 mo. (95% CI 3.5-5.4) v. VS-poor 1.9 mo. (95% CI 1.1-3.4), p=0.014. This was still true after excluding 14 patients who had received cabozantinib alone (p=0.005). There was no difference in PFS for VS-good patients when stratified by EGFRm status. There was also no difference in PFS for VS-poor patients with WT/UNK EGFR v. VS-good patients irrespective of EGFRm status. However, VS-poor patients with WT/UNK EGFR had improved PFS compared to VS-poor patients with an EGFRm (3.1 mo. v. 1.6 mo., HR 0.15, 95% CI 0.03-0.68).

      Conclusion:
      VeriStrat is a strong prognostic marker in this study. This study suggests cabozantinib neutralized the worse prognosis of VS-poor patients with WT/UNK EGFR. Given the heterogeneity of treatment dosing, the small number of VS-poor patients, and a high proportion of unknown EGFRm (including T790M) status, this analysis should be considered exploratory.

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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI14.01 - EGFR-Mutated PDX in NSCLC: Molecular Fidelity and Correlation of PDX and Patient Response to EGFR Inhibition (ID 2191)

      10:45 - 10:50 AM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Background:
      Inevitable emergence of resistance to tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated NSCLC warrants development of pro-active therapeutic strategies to delay or circumvent this evolution. To model such approaches, we are employing a clinically and genomically annotated patient derived xenotransplant (PDX) resource designed to duplicate relevant known mechanisms of resistance to TKI therapy. This analysis examines molecular fidelity and correlates response between patient and PDX in EGFR-mutant NSCLC.

      Methods:
      Six EGFR-mutated NSCLC, 1 EGFR-TKI naïve and 5 after progressive disease on erlotinib, were implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mice as previously described (DR Gandara, Clin Lung Cancer 2015). Models were considered established when PDX growth was confirmed in passage 1 (P1); tumor growth studies were conducted in P3-P5. The donor patient tumor (PT) and the resultant PDX were analyzed for driver mutations (Response Genetics Inc., and Illumina TSCAP), copy number variants (CNV) and global RNA expression (Affymetrix arrays). Informed consent was obtained from all patients. EGFR-mutant PDX treatments included: erlotinib, afatinib, cetuximab, and afatinib+cetuximab. Patient response was graded by RECIST 1.1 and measured in PDX by tumor shrinkage from pre-treatment baseline. In select models, pharmacodynamic studies (kinase arrays; immunoblotting) were also performed.

      Results:
      The EGFR mutation subtypes identified in the donor PT were preserved in all PDX models (4 EGFR E19del and 2 EGFR L858R). Corresponding putative mechanisms of resistance were identical in both PT and PDX in 3 cases: EGFR T790M (2 of 5) and MET amplification (1 of 5). Of 5 post-erlotinib progression PDX models, 3 had progressive disease (PD) and 2 had transient tumor shrinkage to erlotinib. The PDX derived from an erlotinib-naïve patient (EGFR E19del) demonstrated sustained tumor shrinkage to erlotinib. Patient-PDX treatment correlations were possible in 3 post erlotinib-progression models. Two of these patients received afatinib-cetuximab: 1 with partial response (PR) and 1 with PD. The two models corresponding to these patients, when treated with afatinib-cetuximab, underwent complete regression of tumor (CR) and PD, respectively. Pharmacodynamic assessment of the responding model at 24h showed near complete diminishment of pEGFR following afatinib-cetuximab, concomitant with decreased pHer2, pERK, pAKT and p38. Erlotinib showed transient inhibition on signaling in this model at 6h, returning to baseline by 24h. In contrast, the non-responding model showed minimal effects on target inhibition and signal transduction following treatment with any EGFR inhibitor.

      Conclusion:
      Genomic fidelity was preserved in EGFR-mutant PDX, including putative mechanisms of resistance in the post-erlotinib progression models. The majority (3/5) of the EGFR-mutant PDXs created after erlotinib resistance demonstrated PD. In the other post-erlotinib progression models transient tumor shrinkage was noted, which may reflect PDX passaging in the absence of selective pressure of EGFR-inhibition or pharmacokinetic considerations. Overall, the PDX response to treatment reflected the corresponding patient’s clinical course. Pharmacodynamic studies of select models informed PDX response to treatment.

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    MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI17.02 - SWOG 0709: Randomized Phase II Trial of Erlotinib vs. Erlotinib plus Carboplatin/Paclitaxel in Patients (Pts) with Advanced Non-Small Cell Lung Cancer (NSCLC) and Impaired Performance Status (PS2) as Selected by Serum Proteomics (ID 658)

      04:55 - 05:00 PM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Background:
      Advanced NSCLC pts with Zubrod PS2 are often excluded from clinical trials and platinum-based therapy. In SWOG 0341, erlotinib in PS 2 pts yielded progression-free (PFS) and overall survival (OS) of 2.1 and 5 months respectively. In a trial of erlotinib versus carboplatin/paclitaxel in PS2 pts (Lilenbaum, JCO 2008), PFS for erlotinib and chemotherapy were 1.9 and 3.5 months, respectively. Early reports suggested a potential role for serum proteomics in predicting erlotinib benefit beyond that of EGFR mutational status. We therefore conducted a prospective trial of erlotinib +/- chemotherapy in NSCLC pts with PS2 enriched by serum proteomics (Veristrat assay).

      Methods:
      Metastatic NSCLC pts with PS2, acceptable end-organ function, and “good” classification by serum proteomics were randomized to either Arm A (erlotinib 150 mg orally QD) or Arm B (erlotinib 150 mg orally QD on days 2-16 plus carboplatin AUC 5 IV day 1 and paclitaxel 200 mg/m2 IV day 1 x 4 cycles, followed by erlotinib 150 mg orally QD). Cycle length was 3 weeks. Arm B agents were “pharmacodynamically separated” to mitigate potential antagonism. The arm with superior observed median PFS would be selected for further evaluation, but only if ≥ 3 months. A sample size of 98 pts was based on a variety of assumed PFS probabilities for each arm. The trial was prematurely closed after the FDA determined midway through accrual that an IDE application was required for the proteomics assay; however SWOG had limited resources available for such filing.

      Results:
      Of 156 pts screened, 83 (59%) were classified as “good” by serum proteomics. 59 of 83 pts (60%) met trial eligibility and were randomized. Treatment-related grade 4 adverse events were seen in 2 pts in Arm A (thrombosis, hypomagnesemia) and 5 pts in Arm B (neutropenia -5, febrile neutropenia-1, leukopenia -1), with no treatment related deaths. Figure 1



      Conclusion:
      In Zubrod PS2 pts with advanced NSCLC and “good” classification by serum preoteomics, pharmacodynamically-separated erlotinib plus chemotherapy had better observed median PFS/OS versus erlotinib alone and surpassed the protocol-specified benchmark of PFS >= 3 months required for further study. Updated data will be presented.

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    MINI 38 - Biology and Prognosis (ID 167)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI38.06 - FP1039/GSK3052230 with Chemotherapy in Patients with Fibroblast Growth Factor (FGF) Pathway Deregulated Squamous NSCLC or MPM (ID 2879)

      07:00 - 07:05 PM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Background:
      GSK3052230/FP1039 is a soluble fusion protein with the ECD of FGFR1c linked to the hinge and Fc regions of human IgG1 and acts as a ligand trap by sequestering FGFs involved in tumor growth and angiogenesis. In contrast to small molecule FGFR kinase inhibitors, GSK3052230 spares the hormonal FGF ligands, namely FGF19, 21 and 23. GSK3052230 combined with chemotherapy was efficacious in xenograft models of FGFR1-amplified NSCLC and malignant pleural mesothelioma (MPM) with FGF2 mRNA overexpression. A phase I monotherapy study determined 20mg/kg weekly as the maximum feasible dose (MFD) achieving the desired blood concentration, with no maximum tolerated dose (MTD) reached.

      Methods:
      This study (NCT01868022 funded by GSK) will evaluate the safety and efficacy of GSK3052230 weekly infusion in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic sqNSCLC that has progressed after at least 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Each arm involves a dose escalation phase utilizing the 3+3 design, followed by an expansion phase up to 30 patients (pts). Key endpoints include the MTD/MFD of GSK3052230 with chemotherapy, safety, response rates and duration.

      Results:
      Thirty-four pts have been dosed with GSK3052230 at dose levels ranging from 5mg/kg to 20mg/kg in combination with chemotherapy across three Arms, n=15 (A), n=6 (B) and n=13 (C). Baseline characteristics: males/females 29/5; mean age 68.5 years; ECOG PS 0 (n=20), 1 (n=13), 2 (n=1). Most common AEs were: Arm A: asthenia, neutropenia; Arm B: neutropenia, diarrhea, rash; Arm C: decreased appetite, nausea, infusion reaction. Infusion reactions were seen in 8/34 (24%) pts (n=3 Grade (Gr)1, n=3 Gr2, n=2 Gr3). Serious AEs included: Arm A- neutropenia (n=4), fatigue (n=1), asthenia (n=1), fever (n=1), respiratory infection (n=1); Arm B- neutropenia (n=1), abdominal pain (n=1); Arm C-bowel perforation/ischemia (n=1), infusion reaction (n=1), elevated creatinine (n=1). No DLTs have been observed in sqNSCLC pts (Arms A and B). Three DLTs were reported in mesothelioma pts (Arm C 20mg/kg): Gr5 bowel perforation/ischemia, Gr4 elevated creatinine levels and Gr3 infusion reaction. MFD for Arm A is determined at 20mg/kg. Dose escalation is ongoing for Arms B and C. Preliminary PK results revealed no drug-drug interactions. At time of data-cutoff, 10 PR were observed among 23 patients evaluable for efficacy (ORR = 43%) and a clinical benefit rate of 78% with two ongoing subjects on study >300 days. Preliminary efficacy is as follows: Arm A (6 PR, 2 SD, 1 PD, 6= not-yet-evaluable (NE)), Arm B (4 SD, 1 PD, 1 NE), and Arm C (3 PR, 3 SD, 3 PD, 4 NE).

      Conclusion:
      GSK3052230 is in general well tolerated in combination with chemotherapy. The MFD for GSK3052230 is 20mg/kg in combination with paclitaxel + carboplatin in first line sqNSCLC patients. Toxicities typically associated with small-molecule FGFR inhibitors, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. The initial activity and safety profile of GSK3052230 ​warrant further study.

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    MTE 02 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (Ticketed Session) (ID 54)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Advocacy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 AM - 08:00 AM, 105
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      MTE02.01 - Patients, Investigators and Pharmaceuticals Working Together to Accelerate Research and Access: The Lung Cancer Master Protocol (Lung-MAP) Clinical Trial (ID 1979)

      07:00 - 07:30 AM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The traditional obstacles to approval of oncologic therapeutic agents, especially targeted therapies that address a rare-biomarker defined group of patients are the long processes from initial drug discovery to clinical implementation, the difficulties in recruitment for these clinical trials and high number of screen failures and the overall low rate of enrollment in clinical trials. The Lung Master Protocol (Lung-MAP, S1400) is a precedent-setting clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer of the lung (SCCA). There are few new effective therapeutic options for patients with advanced lung SCCA. Immunotherapies, including nivolumab, have already shown clear benefit for patients with SCCA in 2015 leading to approval by the FDA which has been an unprecedented step forward for the treatment of patients, however we are still lacking predictive markers for these therapies that are reliably selecting patients more likely to benefit. Lung-MAP (S1400) is aiming to identify biomarker-drug pairs that will lead to successful therapeutic outcomes and registration of new agents. It is a registration-intent master protocol that includes a screening component and clinical trial component; the clinical trial component includes multiple sub-studies which independently evaluate investigational therapies. The clinical trial component is designed to be modular such that new sub-studies can be added either as other sub-studies close or as new biomarker-drug pairs are identified for testing in this patient population. Lung-MAP is utlilizing a broad NGS screening platform capitalizing on the expanding application of genomic sequencing in oncology that has through the Cancer Genome Atlas and other sequencing initiatives revealed targetable genetic aberrations including gene mutations, rearrangements, amplifications, and deletions, and creating an immense opportunity to implement personalized therapy with a high potential to improve patients outcomes. Immunotherapy has been integrated in the design of Lung-MAP from its launch in June of 2014. The original study design and structure is shown in the figure. Figure 1 The modular design of the study has allowed for the flexibility to adapt to the approval of nivolumab and the hault in further development of AMG102 (rilotumumab) with discontinuation of the corresponding sub-study by implementing timely modifications which include the following:1)Eligibility has changed from exclusively second line therapy to second-or more line therapy 2)Pre-screening, while patient receive first line therapy has been added to boost accrual 3)the unmatched arm has been changed to a single (not randomized) arm study with the anti-PD-L1 agent MEDI-4736. Theses changes are reflected in the figure. Each independently conducted and analyzed sub-study specifies investigator-assessed progression-free survival (IA-PFS) and overall survival (OS) as the co-primary endpoints for the phase 3 primary objectives. The primary objectives for the phase 3 are to determine if there is a statistically significant difference in OS and to determine if there is both a clinically meaningful and statistically significant difference in IA-PFS. The conduct of Lung-MAP relies on close collaboration (a public-private partnership) among the NCI and NCTN (spearheaded by SWOG), the pharmaceutical industry, the Foundation for the NIH (FNIH), Friends of Cancer Research, advocates, and FDA. This Master Protocol will improve genomic screening of SCC patients for clinical trial entry, and improve time lines for drug-biomarker testing, allowing for inclusion of the maximum numbers of otherwise eligible patients. The clinical trial continues to be updated following science and alterations in the therapeutic landscape, with adaptations in design and incorporation of new agents against matched targets and the implementation of novel immunotherapy approaches for the unmatched arm. Figure 2





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    ORAL 10 - SCLC (ID 98)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      ORAL10.05 - Discussant for ORAL10.01, ORAL10.02, ORAL10.03, ORAL10.04 (ID 3560)

      11:49 - 11:59 AM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 17 - EGFR Mutant Lung Cancer (ID 116)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL17.06 - Phase I/II Study of INC280 plus Erlotinib in Patients with MET Expressing Adenocarcinoma of the Lung (ID 1064)

      11:39 - 11:50 AM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Background:
      MET dysregulation is one mechanism responsible for EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance in patients (pts) with EGFR mutated lung cancer. INC280 is a potent oral small molecular inhibitor of the c-MET kinase. We conducted a phase I/II study of INC280 plus erlotinib to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of this combination. Tumor analysis of the EGFR and MET pathways was exploratory.

      Methods:
      Using a 3 + 3, dose escalation design, INC280 was increased over 5 dose levels (DL) from 100 - 600 mg po bid. Daily erlotinib was given at 100 mg in DL1 and 150 mg in DL 2- 6. DL 6 is a transition cohort from INC280 capsules (600 mg) to tablets (400 mg). Both agents were given for 28 days (1 cycle). Key eligibility included: lung adenocarcinoma with MET expression by a CLIA certified lab, age > 18, ECOG PS of < 2, acceptable organ function, and > 1 systemic therapy for advanced disease.

      Results:
      18 pts were treated on 6 dose levels. Pt characteristics: median age 59 (range 52-78), M/F (7/11), ECOG 0-1/2 (16/2), MET expression by IHC/FISH/RT-PCR/NGS (6/2/9/1), EGFR mutated tumors (9) and previously treated with erlotinib (12). 17 patients completed at least 1 cycle. One DLT (grade 3 neutropenia) occurred in DL 5 (Table 1). Common drug-related adverse events (AE) of any grade were rash (50%) and diarrhea (45%), fatigue (39%), anorexia and nausea (28% each) and increased alkaline phosphatase, hypoalbuminemia and paronychia (22% each). Drug-related grade 3/4 AE were anorexia, increased amylase or lipase and neutropenia (all 6%). PK analysis revealed that INC280 exhibited a linear PK and no interaction with erlotinib. Of the 17 evaluable patients, 3 (18%) patients had partial responses, 10 (59%) had stable disease, 3 of whom had a minor response (10-29% decrease in target lesion) (Table 1). Eight pts have received treatment for >3 months. Figure 1



      Conclusion:
      In patients with MET-expressing lung adenocarcinoma, INC280 plus erlotinib is feasible, tolerable and demonstrates anti-tumor activity. The recommended phase 2 doses are INC280 400 mg (tablets) bid plus erlotinib 150 mg daily. Three expansion cohorts have been initiated: 1 - EGFR mutated tumors refractory to an EGFR-TKI, 2 - EGFR-TKI naïve in the first line setting and 3 - WT EGFR that are EGFR-TKI naïve as second or third line therapy. Updated trial results from the expansion cohorts will be presented. NCT01911507

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    ORAL 18 - Non PD1 Immunotherapy and Angiogenesis (ID 114)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL18.07 - Discussant for ORAL18.04, ORAL18.05, ORAL18.06 (ID 3336)

      11:50 - 12:00 PM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 38 - Liquid Biopsies (ID 147)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL38.06 - Identification of Actionable Tumor Alterations in Circulating Cell-Free Tumor DNA (cf DNA) Using Digital Sequencing from NSCLC Patients (ID 1706)

      05:39 - 05:50 PM  |  Author(s): P. Lara Jr.

      • Abstract
      • Presentation
      • Slides

      Background:
      To fully implement precision therapy in lung cancer, transition to a re-biopsy policy will be required at baseline and at progression after each line of therapy. The molecular testing paradigm is shifting toward next generation sequencing (NGS). As tissues are limited and repeat invasive biopsy introduces cost and risk, novel technologies sensitive and specific enough for multiplexed assessment in cell-free DNA (cfDNA) isolated from patient blood would represent a significant advance. Preliminary experience from investigators suggest a high degree of correlation between repeat tumor biopsy and plasma NGS. Here, we present the Guardant Health (GH) digital sequencing approach in a consecutive series of NSCLC cases.

      Methods:
      225 consecutive blood specimens from NSCLC patients, collected February–March 2015, were evaluated for cfDNA tumor alterations by digital sequencing using the GH panel of 68 genes. The test includes all reported fusion partners for ALK, RET, ROS1, and NTRK1 and cfDNA amplification for 16 genes. The mutant allele fraction (MAF) was calculated relative to WT in cfDNA. The test is sensitive to a single fragment of mutated cfDNA in a 10 ml blood sample and analytic specificity is >99.9999%.

      Results:
      Canonical EGFR activating mutations were detected in 20 cases (14 E19del, 3 L858R, 2 E20ins, 1 G719A). EGFR T790M co-occurred in 7 cases (6 E19del, 1 L858R), with EGFR amplification observed in 6 of the 20. Median age for patients with EGFR mut+ was 62.5; 18 female(90%), compared to nonEGFR-mutant cases. Four cases had driver fusions (2EML4-ALK, 2 KIF5B-RET) and five cases harbored an ERBB2 E20ins. KRAScodon 12/13 mutations were detected in 23 patients, while 3 harbored mutations in HRAS(Q61L) and NRAS(Q61L, G13R), and 6 had BRAF mutations (4 V600E, 2 G466X). All putative drivers were mutually exclusive. Mutations in signal transduction factors with confirmed gain-of-function activity included AKT1(E17K), MEK1(K57N, C121S), PIK3CA(E542K, E545K x2, H1047L, M1043V, R93W) and JAK2(V617F x2); truncating or missense mutations (>3% MAF) were observed in NF1 (6 cases), PTEN(1 case), SMAD4(4 cases) and STK11(4 cases). TP53 mutations were detected in 116/225 (51%). Evidence of gene amplification was seen in 32 cases, with 11 harboring multiple events. By function, amp events were observed for G1 cell cycle factors:11, RTKs: 17, MYC: 2; and signal transduction: 21. MAF ranged from 0.06% to 83.4% (av 5.1%; median: 9.8%), reflecting clinical and biologic diversity of patients. In a clinical subset at UC Davis, 27 patients were evaluated and alterations were detected in 18 (66.7%). Actionable findings were identified in 14 (77.8%) including 2 with EGFRL858R, 1 with EGFR E19del, and 1 interesting case with EGFR E19del at 45% MAF, EGFR amplification, and an emerging EGFR T790M clone at 0.54% MAF.

      Conclusion:
      In a series of NSCLC cases, high-sensitivity, high-specificity cfDNA analysis demonstrated the ability to identify somatic tumor alterations, including clinically actionable predictors, in a majority of patients via a simple blood draw, suggesting that this approach can be used for guiding therapeutic decision-making when repeat biopsy is high risk or not possible. Assuming validation, plasma cfDNA analysis may supplant invasive tumor biopsy in the near future.

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    P1.07 - Poster Session/ Small Cell Lung Cancer (ID 221)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      P1.07-014 - Predictors of Survival in Small Cell Lung Cancer (SCLC) Patients (pts) < 50 Years of Age: Results from the California Cancer Registry (CCR) (ID 2416)

      09:30 - 09:30 AM  |  Author(s): P. Lara Jr.

      • Abstract
      • Slides

      Background:
      SCLC is an often lethal disease that commonly occurs in older individuals with a history of heavy tobacco use. Limited epidemiologic and outcomes data are available for young SCLC pts (< 50 years of age). We analyzed the CCR to explore the clinical variables related to cause specific survival (CSS) of young pts.

      Methods:
      SCLC pts diagnosed between 1998-2012 were included. Primary outcome was CSS. Hazard ratios (HR) for CSS were calculated using Cox Proportional Hazards (PH) models for all ages & for pts <50 years, adjusted for baseline variables: age, gender, stage, race, year of diagnosis, treatment, socioeconomic status (SES), and location (urban vs. rural).

      Results:
      We identified 22,863 SCLC pts, of which 975 were <50 years of age (4.2%). Demographics for pts <50 years: Males-51%; White-71%; Stage IV-60%; Chemotherapy-79%; Urban location-92%; high SES-28%. Fewer pts < 50 years were diagnosed in later years: from 40% in ‘98-’02 to 24% in ‘08-‘12. Results of multivariate Cox PH models are shown. (HR=Hazard Ratio).

      Select Variables All pts Pts<50 years of age
      HR P-value HR P-value
      Age at diagnosis (vs. ≥50yrs) 0.82 <0.0001 N/A N/A
      Female sex (vs.Male) 0.91 <0.0001 0.81 0.0045
      Race (vs.White)
      Asian 0.84 <0.0001 0.57 0.0075
      Year of Dx (vs.'88-'02)
      2003-'07 0.96 0.0096 0.95 0.5562
      2008-'11 0.94 0.0017 0.89 0.2796
      Stage (vs.I)
      Stage II 1.22 0.0111 1.20 0.7255
      Stage III 1.80 <0.0001 1.81 0.0282
      Stage IV 2.93 <0.0001 3.81 <0.0001
      Treatment (vs.None)
      Surgery 0.43 <0.0001 0.37 0.004
      Chemotherapy 0.44 <0.0001 0.49 <0.0001
      Radiation 0.66 <0.0001 0.71 <0.0001
      Rural (vs.Urban) 0.97 0.3042 0.75 0.0419
      Low SES {vs.High SES(4,5)} 1.05 0.0011 1.04 0.6306


      Conclusion:
      Age < 50 years was an independent predictor of improved CSS (HR 0.82, p<0.0001). In younger pts, female sex (HR 0.81, p=0.0045), Asian race (HR 0.57, p=0.0075), and rural residence (HR 0.75, p=0.042) were associated with better CSS, among other variables. Analyses for relevant interactions within subgroups will be presented.

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